This invention relates to a medical-use adhesive that is used for bonding of living tissues, filling or preventing of adhesion between living tissues, or for stopping of bleeding, after surgical operation or the like, as well as a medical-use resin. Especially, the invention relates to an adhesive that cures after mixing of first and second liquids and then decomposes to be fluidized after elapse of a certain period.
As an adhesive for medical use, especially for surgical operation; (1) cyanoacrylate adhesives and (2) fibrin glue have been predominantly used.
(1) Cyanoacrylate Adhesive
The cyanoacrylate adhesive has been used in industrial use and household use, for original purpose of instantly adhering of; metal, plastics, rubber, wood, ceramics or the like. About ten varieties of the cyanoacrylate adhesive for medical use had been developed by year of 1968. This category of adhesive utilizes that; cyanoacrylate monomers are polymerized and cured in presence of a small amount of water that is a polymerization initiator. And, the polymerization and curing are rapid, and strength of adhesion on living tissues are high. However, cured resin has poor flexibility and is rigid and may thereby deter healing of wounds. Moreover, the cured resin is difficult to be decomposed as to be remained as a foreign body after being enveloped. Further, there has happened to be reported that formaldehyde is produced on way of decomposition of the resin as to exhibit cytotoxicity and/or injuring on tissue.
(2) Fibrin Glue
Fibrinogen forms fibrin masses by action of thrombin; such mechanism of coagulation of blood is utilized in this category of adhesive. The fibrin glue has high compatibility with living body and high convenience in usage and is widely used in arresting of bleeding from a suture part or the like after surgical operation and in enhancing of bonding and closure of tissues. The fibrin glue however has only poor level of adhesive strength so that produced fibrin masses may be occasionally peeled off from the tissue. Moreover, due to being a blood product, there remains a fear of virus transmission.
On the other hand, two-liquid adhesives for surgical use as in (3)-(6) below have been recently proposed.
(3) Dextranaldehyde (oxidized dextran being a polyaldehyde)/high-molecular-weight chitosan—WO 2003/035122 of AESCULAP AG & CO KG (DE); a counterpart of U.S.2005/0002893 A-1 and EP 143 8079 B1.
There has been proposed a two-liquid reaction adhesive for surgical use; a first liquid of which is 15 wt % aqueous solution of dextranaldehyde; and a second liquid of which is 2 wt % or 4 wt % aqueous solution of high-molecular-weight chitosan (Protasan™ UPCL213, FMC Biopolymers). In the adhesive, molar ratio of aldehyde groups to amino groups (aldehyde/amino molar ratio) is “at least three” according to a sole independent claim 1; and curing within 150 seconds was achieved by adopting the aldehyde/amino molar ratios of no less than 6, which are calculated from Table 2 and Table 1. Meanwhile, Table 3 and so on indicate that achieved shear strength was sufficient; and Table 8 indicates that more excellent adhesive strength was achieved by use of high-molecular-weight dextran having an average molecular weight no less than 400,000.
Moreover, last section (“4. Stoppage of Liver Bleeding”) of the description indicates that; a two-part reactive adhesive having the aldehyde/amino molar ratio of 13.6 (“DA6” on Table 3), with first liquid to second liquid mixing ratio of 1/1, was effective as haemostatic sealant for rat liver. Curing time of this adhesive was about 15 seconds according to Table 2.
Tables 6 and 7 as well as explanations relevant to these tables indicates that sufficient adhesion strength was achieved even when 20 wt % aqueous solution of polyvinylalcohol-vinylamine graft copolymer (PVALNH2) is used in place of the chitosan aqueous solution. However, molecular weight and composition of the used copolymer were not specified. The curing time was also not specified.
(4) Micelle-forming polymer with aldehyde end groups/high-molecular-weight polyallylamine—JP-2005-021454A; NISHIDA, Hiroshi; YOKOYAMA, Masayuki, “Tissue adhesive formed of polymer micelle as effective component”.
JP-2005-021454A discloses two-part reactive “adhesive for animal tissues”. Its first liquid is aqueous micelle solution of a polymer having following structure; [end-aldehyde group]-[polyethylene glycol segment having molecular weight of 5500]-[polylactide segment having molecular weight of 4000]. Second liquid of the adhesive is aqueous solution of high-molecular-weight (no less than 60,000) polyallylamine.
It is indicated that; aqueous solution of poly-L-lysine (Table 3 as well as RUN 13-14 and 16 of Table 5) and chitosan aqueous solution (Table 4) may be used as the second liquid, in place of the polyallylamine solution. Paragraph 0031 indicates that oxidized starch and oxidized cellulose may be used for the first liquid. In respect of the poly-L-lysine, RUN 13-14 and 16 of Table 5 indicate that; high molecular weight of 700,000 is needed and a relatively low molecular weight of 30,000 is not adoptable. Moreover, Table 3 as well as RUN 12-16 of Table 5 indicates that; pH of the polylysine aqueous solution as the second liquid has to be no less than 9.0.
(5) Starch aldehyde (oxidized starch being a polyaldehyde)/collagen—WO98/15299; “ADHESIVE COMPOSITION WITH MACROMOLECULAR POLYALDEHYDE BASE AND METHOD FOR CROSS-LINKING COLLAGEN”; a counterpart of Japan's issued patent 323871.
As a first liquid, 0.5 ml of 5 wt % aqueous solution of solubilized starch that has been oxidized to form a polyaldehyde; please see first sentence of Example 3. Molecular weight of the solubilized starch “may be varied in a range of 10,000 to 200,000 dalton” as read from Example 1. While molecular weight of collagen is not mentioned in the specification, the molecular weight is thought to be about 300,000 as in typical collagens. The adhesive is described to be useful in bonding tissues of living body and to have ability for preventing adhesion among tissues. Please see Examples 3-6.
(6) Gelatin/succinimidized poly-L-glutamate—JP-9 (1997)-103479 “Medical-use material and its production method”.
Aqueous solution containing the gelatin, which is produced by heat-denaturing of collagen, is used as a first liquid; and, an aqueous solution containing succinimidized poly-L-glutamic acid is used as a second liquid; according to a disclosed medical-use adhesive.
Meanwhile, other than the two-part adhesives mentioned above, there have also been proposed medical-use adhesives as in (7)-(8) below.
(7) Gelatin/Dicarboxylic Acid
Gelatin is reacted with dicarboxylic acid as to convert amino groups of the gelatin into carboxylic groups. Such adhesive is disclosed. Please see JP-11 (1999)-239610A (“Medical-use material for bonding tissues of living body as well as production method thereof”). Medical-use adhesives based on the gelatin causes fear of BSE or the like due to use of risk portions of cattle, and hence are avoided to be used in clinical practice.
(8) Urethane Polymer
For example, there is disclosed an adhesive formed of an adduct that is produced by polyol and polyisocyanate. Please see JP2004-261590A (“Medical-use adhesive”). This adhesive has disadvantages in difficulty of handling due to high viscosity and in difficulty of adhesion at portions having lot of blood or body fluid.